A dose-ranging study of the physiological and self-reported effects of repeated, rapid infusion of remifentanil in people with opioid use disorder and physical dependence on fentanyl.

RATIONALE: Understanding mechanisms of drug use decisions will inform the development of treatments for opioid use disorder (OUD). Decision-making experiments using neurobehavioral approaches require many trials or events of interest for statistical analysis, but the pharmacokinetics of most opioids limit dosing in humans. OBJECTIVES: This experiment characterized the effects of repeated infusions of the ultra-short acting opioid remifentanil in people with OUD and physical opioid dependence. METHODS: An inpatient study using a within-subjects, single-blind, escalating, within-session, pre-post design was conducted. Seven (3 female) subjects were maintained on oral oxycodone (40-60 mg, 4x/day = 160-240 total mg/day) for seven days prior to the dose-ranging session. Subjects received infusions of three ascending remifentanil doses (0.03, 0.1, 0.3 mcg/kg/infusion in 2 subjects; 0.1, 0.3, 1.0 mcg/kg/infusion in 5 subjects) every minute for 40 min per dose, with infusions administered over 5 s to model naturalistic delivery rates. End tidal carbon dioxide, respiration rate, oxygen saturation (SpO2) and heart rate were measured continuously. Blood pressure (BP), pupil diameter and self-reported drug effects were measured every 5 min. RESULTS: Pupil diameter, SpO2 and systolic BP decreased, and ratings on prototypic subjective effects questionnaire items increased, as a function of remifentanil dose. The number of infusions held because of sedation or physiological parameters exceeding predetermined cutoffs also increased with dose. CONCLUSIONS: This experiment established doses and procedures for the safe delivery of rapid, repeated remifentanil infusions to individuals with OUD and physical fentanyl dependence, which can be applied to the mechanistic study of opioid use decisions.

Adverse childhood experiences and early initiation of substance use: A survival analysis.

OBJECTIVE: Early adversity, such as adverse childhood experiences (ACEs), is a risk factor for the development of substance use disorder (SUD). ACEs are associated with earlier initiation of substance use. This study examined the relationship between ACEs and age of initiation of substance use using survival analysis. It is hypothesized that individuals with higher ACEs will have an earlier age of initiation. METHOD: Participants were recruited from the University of Kentucky's Laboratory for Human Behavioral Pharmacology. Participants were 18 years or older, English speaking, and actively engaged in substance use. Participants were not in substance abuse treatment nor were they seeking treatment. ACE scores were calculated, and age of substance use initiation was recorded. A Cox proportional hazard model was used to examine the effect of ACE score on age of substance use initiation. RESULTS: A total of 107 participants completed the study. An average number of 2.3 ACEs (SD = 2.2) were endorsed with 24% of participants reporting 4 or more ACEs. Higher ACE scores were associated with cigarette smoking and non-medical prescription opioid use onset ( hazard ratio (HR) = 1.14, 95% CI=1.02-1.28, p = 0.02, and HR=1.19, 95% CI = 1.04-1.37, p = 0.01, respectively. CONCLUSIONS: A significant association was found between higher ACE scores and earlier initiation of cigarette and non-medical prescription opioid use, consistent with prior research. Primary prevention of ACEs, screening for ACEs during childhood, and interventions for ACEs if detected, may help to reduce the risk of substance use/SUD in adulthood.

Use of drug purchase tasks in medications development research: orexin system regulation of cocaine and drug demand.

Commodity purchase tasks provide a useful method for evaluating behavioral economic demand in the human laboratory. Recent research has shown how responding to purchase tasks for blinded drug administration can be used to study abuse liability. This analysis uses data from a human laboratory study to highlight how similar procedures may be particularly useful for understanding momentary changes in drug valuation when screening novel interventions. Eight nontreatment-seeking participants with cocaine use disorder (one with partial data) were enrolled in a cross-over, double-blind, randomized inpatient study. Participants were maintained on the Food and Drug Administration-approved insomnia medication suvorexant (oral; 0, 5, 10, 20 mg/day) in randomized order with experimental sessions completed after at least 3 days of maintenance on each suvorexant dose. Experimental sessions included administration of a sample dose of 0, 10 and 30 mg/70 kg intravenous cocaine. Analyses focused on purchase tasks for the blinded sample dose as well as alcohol, cigarettes and chocolate completed 15 min after the sample dose. As expected based on abuse liability, near zero demand was observed for placebo with dose-related increases in cocaine demand. Suvorexant maintenance increased cocaine demand in a dose-related manner with the greatest increase observed for the 10 mg/kg cocaine dose. Increased demand under suvorexant maintenance was also observed for alcohol. No effect of cocaine administration was observed for alcohol, cigarette, or chocolate demand. These data support the validity of demand procedures for measuring blinded drug demand. Findings also parallel self-administration data from this study by showing increases in cocaine use motivation under suvorexant maintenance.

Naltrexone-bupropion combinations do not affect cocaine self-administration in humans.

The FDA has not yet approved a pharmacotherapy for cocaine use disorder despite nearly four decades of research. This study determined the initial efficacy, safety, and tolerability of naltrexone-bupropion combinations as a putative pharmacotherapy for cocaine use disorder. Thirty-one (31) non-treatment seeking participants with cocaine use disorder completed a mixed-design human laboratory study. Participants were randomly assigned to the naltrexone conditions (i.e., 0, 50 mg/day; between-subject factor) and maintained on escalating doses of bupropion (i.e., 0, 100, 200, 400 mg/day; within-subject factor) for at least four days prior to the conduct of experimental sessions. Cocaine self-administration (IN, 0, 40, 80 mg) was then determined using a modified progressive ratio and relapse procedure. Subjective and cardiovascular effects were also measured. Cocaine produced prototypical dose-related increases in self-administration, subjective outcomes (e.g., "Like Drug"), and cardiovascular indices (e.g., heart rate, blood pressure) during placebo maintenance. Naltrexone and bupropion alone, or in combination, did not significantly decrease self-administration on either procedure. Low doses of bupropion (i.e., 100 mg) blunted the effects of the cocaine on subjective measures of "Like Drug" and "Stimulated". No unexpected adverse effects were observed with naltrexone and bupropion, alone and combined, in conjunction with cocaine. Together, these results do not support the use of these bupropion-naltrexone combinations for the treatment of cocaine use disorder. Future research should determine if novel drug combinations may decrease cocaine self-administration.

Suvorexant maintenance enhances the reinforcing but not subjective and physiological effects of intravenous cocaine in humans.

Preclinical research has sought to understand the role of the orexin system in cocaine addiction given the connection between orexin producing cells in the lateral hypothalamus and brain limbic areas. Exogenous administration of orexin peptides increased cocaine self-administration whereas selective orexin-1 receptor antagonists reduced cocaine self-administration in non-human animals. The first clinically available orexin antagonist, suvorexant (a dual orexin-1 and orexin-2 receptor antagonist), attenuated motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding, in rodents. This study aimed to translate those preclinical findings and determine whether suvorexant maintenance altered the pharmacodynamic effects of cocaine in humans. Seven non-treatment seeking subjects with cocaine use disorder completed this within-subject human laboratory study, and a partial data set was obtained from one additional subject. Subjects were maintained for at least three days on 0, 5, 10 and 20 mg oral suvorexant administered at 2230 h daily in random order. Subjects completed experimental sessions in which cocaine self-administration of 0, 10 and 30 mg/70 kg of intravenous cocaine was evaluated on a concurrent progressive ratio drug versus money choice task. Subjective and physiological effects of cocaine were also determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g., increased ratings of "Stimulated" and heart rate). Suvorexant (10, 20 mg) increased self-administration of 10 mg/70 kg cocaine and decreased oral temperature but did not significantly alter any other effects of cocaine. Future research may seek to evaluate the effects of orexin-1 selective antagonists in combination with cocaine.

Topiramate-phentermine combinations reduce cocaine self-administration in humans.

RATIONALE: Cocaine use disorder is an unrelenting public health concern. Despite nearly four decades of research, an FDA approved medication is not yet available. OBJECTIVES: The objective of this human laboratory study was to demonstrate the initial efficacy, safety and tolerability of topiramate-phentermine combinations for cocaine use disorder. METHODS: Thirty-one (31) participants with cocaine use disorder completed this mixed-model inpatient laboratory study. Participants were maintained on topiramate (0 [N = 11], 50 [N = 9] or 100 [N = 11] mg/day). Each topiramate group was concurrently maintained on phentermine (0, 15, 30 mg). Drug self-administration, subjective responses and cardiovascular effects following acute doses of intranasal cocaine (0, 40, 80 mg) were determined during separate experimental sessions after at least seven (7) days of maintenance on each condition. RESULTS: The three groups of participants were well matched demographically and generally did not differ significantly in their responses to a range of doses of intranasal cocaine (0, 10, 20, 40, 80 mg) during a medical safety session. Maintenance on topiramate and phentermine alone significantly decreased cocaine self-administration although these effects were modest in magnitude. Combining topiramate and phentermine robustly decreased cocaine self-administration. Topiramate and phentermine were well tolerated alone and combined, as well as in conjunction with cocaine. CONCLUSIONS: The results of the present study support advancing topiramate-phentermine combinations as a putative pharmacotherapeutic for cocaine use disorder.

Influence of n-acetylcysteine maintenance on the pharmacodynamic effects of oral ethanol.

RATIONALE: Glutamate systems play an important role in the abuse related effects of alcohol. n-Acetylcysteine, a drug that promotes glutamate homeostasis, attenuates a range of alcohol effects in preclinical models. OBJECTIVES: This human laboratory study determined the influence of n-acetylcysteine maintenance on alcohol self-administration using a model predictive of treatment effectiveness, along with the subjective, performance and physiological effects of alcohol. We hypothesized that n-acetylcysteine would attenuate alcohol self-administration, as well as positive subjective effects of alcohol. METHODS: Nine subjects with alcohol use disorder completed this within-subjects study. Subjects were maintained on placebo, 1.2 and 2.4 g n-acetylcysteine in random order on an outpatient basis. After five days of maintenance on the target dose, subjects completed overnight inpatient experimental sessions in which the pharmacodynamic effects of alcohol were determined. RESULTS: Alcohol produced prototypic effects (e.g., increased breath alcohol concentration, increased ratings of Feel Drink). n-Acetylcysteine did not alter the effects of alcohol. CONCLUSIONS: These results indicate that although n-acetylcysteine can safely be combined with alcohol, it does not attenuate the abuse related effects of alcohol and is unlikely to be an effective standalone alcohol use disorder treatment. However, considering study limitations, future work is needed to further understand whether and how n-acetylcysteine might be used as a treatment for alcohol use disorder (e.g., in combination with a behavioral treatment or another pharmacological agent).

Diffuse optical assessment of cerebral-autoregulation in older adults stratified by cerebrovascular risk.

Diagnosis of cerebrovascular disease (CVD) at early stages is essential for preventing sequential complications. CVD is often associated with abnormal cerebral microvasculature, which may impact cerebral-autoregulation (CA). A novel hybrid near-infrared diffuse optical instrument and a finger plethysmograph were used to simultaneously detect low-frequency oscillations (LFOs) of cerebral blood flow (CBF), oxy-hemoglobin concentration ([HbO2 ]), deoxy-hemoglobin concentration ([Hb]) and mean arterial pressure (MAP) in older adults before, during and after 70° head-up-tilting (HUT). The participants with valid data were divided based on Framingham risk score (FRS, 1-30 points) into low-risk (FRS ≤15, n = 13) and high-risk (FRS >15, n = 11) groups for developing CVD. The LFO gains were determined by transfer function analyses with MAP as the input, and CBF, [HbO2 ] and [Hb] as the outputs (CA ∝ 1/Gain). At resting-baseline, LFO gains in the high-risk group were relatively lower compared to the low-risk group. The lower baseline gains in the high-risk group may attribute to compensatory mechanisms to maintain stronger steady-state CAs. However, HUT resulted in smaller gain reductions in the high-risk group compared to the low-risk group, suggesting weaker dynamic CAs. LFO gains are potentially valuable biomarkers for early detection of CVD based on associations with CAs.

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome Presenting as New-Onset Psychosis in a 32-Year-Old Man: A Case Report and Literature Review.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant disorder caused by mutations in the nuclear receptor subfamily 2 group F member 1 (NR2F1) gene. Its common features include optic atrophy and/or hypoplasia, developmental delay, intellectual disability, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, hypotonia, and thinning of the corpus callosum. Mitochondrial involvement has also been described with BBSOAS. Currently, 31 cases of BBSOAS have been described in the literature. Here we report a case of undiagnosed BBSOAS presenting as psychosis in a 32-year-old man with a history of bilateral optic nerve atrophy, intellectual disability, epilepsy, and mitochondrial complex I abnormality on muscle biopsy. Whole-genome sequencing identified a heterozygous de novo nonsense mutation in the NR2F1 gene [c.253 G>T (guanine to thymine mutation in coding position 253) in exon 1, p.E85X variant (GAG>TAG) (glutamic acid to stop codon mutation; protein truncated to 85 amino acids)]. A pathogenic nonsense mutation has not previously been reported in the literature in association with BBSOAS and represents an expansion of clinically relevant variants. Psychosis has also not been previously reported in this syndrome and may represent a phenotypic expansion of BBSOAS, a manifestation of prolonged disease, or a result of disease management.

Pharmacological validation of a translational model of cocaine use disorder: Effects of d-amphetamine maintenance on choice between intravenous cocaine and a nondrug alternative in humans and rhesus monkeys.

Drug self-administration procedures are the gold standard for laboratory research to study mechanisms of drug use disorders and evaluate candidate medications. However, preclinical-to-clinical translation has been hampered by a lack of coordination. To address this limitation, we previously developed homologous intravenous (IV) cocaine choice self-administration procedures in rhesus monkeys and humans, and then demonstrated their functional equivalence. The present studies sought to determine the sensitivity of these procedures to d-amphetamine maintenance. Three (N = 3) rhesus monkeys with histories of cocaine self-administration and 16 (N = 16) humans with cocaine use disorder completed the studies. Monkeys were maintained on IV d-amphetamine (0, 0.019, 0.037 and 0.074 mg/kg/h), and then completed 7 sessions during each condition in which they completed 9 choice trials to receive 0.14 mg/kg/injection IV cocaine (corresponding to 10 mg/70 kg in humans) or 10 food pellets under independent, concurrent progressive-ratio schedules. Humans were maintained on oral extended release d-amphetamine (0, 30 and 60 mg/day, corresponding to the lowest 3 doses in monkeys) and participated in 12 sessions in which they chose money ($6.00) or IV cocaine (0, 3, 10 and 30 mg/70 kg). Blood samples were taken to compare d-amphetamine plasma levels across species. In monkeys and humans, d-amphetamine reduced the number of cocaine choices and produced comparable blood levels at equivalent daily doses. d-Amphetamine had similar efficacy, though lower potency, at reducing choice for an equivalent cocaine dose in monkeys relative to humans. These coordinated studies support the utility of these procedures as a translational model for cocaine use disorder. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Adverse Childhood Experiences, Tobacco Use, and Obesity: A Crowdsourcing Study.

Background: Exposure to adverse childhood experiences (ACEs) increases health risk behavior in adulthood and is a risk for premature mortality. For example, ACEs are associated with both tobacco smoking and obesity, which remain significant health challenges for many adults, despite widespread knowledge about the risks. Objective: The present investigation used a novel online crowdsourcing platform (Amazon.com mechanical turk) to study the relationship between ACEs and later tobacco smoking and obesity. Methods: Participants were recruited based on smoking (n = 74 smokers; n = 75 nonsmokers) and stratified based on obesity (n = 52 BMI ≥ 30; n = 97 BMI < 30). Participants had no recent history of other substance use, except alcohol. The relationship between ACE score and smoking and obesity categories was analyzed using logistic regression. Results: The average age of the sample was 38.6-years old and was mostly female (66.4%), employed (82.6%) and college educated (63.1%). Those with 4+ ACEs had a significantly greater odds of cigarette use. Any ACEs exposure was associated with a significantly greater odds of obesity. Conclusions/Importance: Findings are concordant with previous studies and suggest crowdsourcing is a viable platform for studying ACEs and health behavior. Access to large samples and specific populations provided by crowdsourcing could help examine theoretical models about how exposure to ACEs could be connected to later adoption of high-risk behaviors such as tobacco cigarette smoking and obesity.

Influence of phendimetrazine maintenance on the reinforcing, subjective, performance, and physiological effects of intranasal cocaine.

RATIONALE: No pharmacotherapies are approved for cocaine use disorder. Phendimetrazine, a prodrug of the monoamine-releaser phenmetrazine, attenuates the reinforcing effects of cocaine in preclinical models, has minimal abuse potential, and is safe when combined with cocaine. OBJECTIVES: This study determined the influence of phendimetrazine maintenance on the reinforcing effects of cocaine (i.e., choice to self-administer cocaine), along with the subjective, performance, and physiological effects of cocaine. We hypothesized that phendimetrazine would attenuate the reinforcing effects of cocaine. METHODS: Twenty-nine subjects with cocaine use disorder completed this within-subject, inpatient study. The subjects were maintained on placebo and 210 mg phendimetrazine in a counterbalanced order. After at least 7 days of maintenance on the target dose, the subjects completed experimental sessions in which the effects of single doses of 0, 20, 40, and 80 mg of intranasal cocaine were determined. RESULTS: Cocaine functioned as a reinforcer, producing significant dose-related increases in self-administration. Cocaine increased prototypic effects (e.g., ratings of stimulated and blood pressure). Phendimetrazine attenuated ratings on a select set of subjective outcomes (e.g., ratings of talkative/friendly), but failed to reduce the reinforcing effects of cocaine or a majority of positive subjective cocaine effects. Phendimetrazine increased heart rate, indicating a physiologically active dose was tested, but heart rate increases were not clinically significant. CONCLUSIONS: These results indicate that although phendimetrazine can safely be combined with cocaine, it does not attenuate the abuse-related effects of cocaine. It is unlikely, then, that phendimetrazine will be an effective standalone treatment for cocaine use disorder.

N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order.

BACKGROUND: Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. METHODS: The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. RESULTS: Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. CONCLUSIONS: These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues.

Safety and tolerability of intranasal cocaine during phendimetrazine maintenance.

RATIONALE: Phendimetrazine appears to have limited abuse potential and reduces cocaine self-administration in preclinical studies. No human studies have evaluated the safety and tolerability of cocaine in combination with phendimetrazine, which is a necessary next step in evaluating the efficacy of phendimetrazine for treating cocaine use disorder. OBJECTIVES: This study determined the safety and tolerability of acute cocaine doses during chronic phendimetrazine treatment. METHODS: Ten subjects completed this within-subject, placebo-controlled, inpatient study. Subjects were maintained on ascending oral phendimetrazine doses (0, 70, 140, and 210 mg/day). After at least seven maintenance days at each dose, subjects received ascending doses of intranasal cocaine (0, 10, 20, 40, and 80 mg), separated by 90 min, within one session. RESULTS: Cocaine produced prototypical cardiovascular and subject-rated effects (e.g., increased blood pressure and ratings of like drug). The cardiovascular effects of cocaine alone were not clinically significant for an acute drug response (e.g., average heart rate did not approach tachycardia, 100 beats/min). Phendimetrazine enhanced peak heart rate following placebo and low cocaine doses, but these effects were also not clinically significant. Phendimetrazine was otherwise devoid of effects alone and did not alter the subject-rated effects of cocaine or hypothetical demand for cocaine on a purchase task. CONCLUSIONS: Cocaine was safe and well tolerated during maintenance on a threefold range of phendimetrazine doses. Given this safety profile, the reduced abuse potential of phendimetrazine and promising preclinical research, future human laboratory studies, and possibly clinical trials should evaluate the efficacy of phendimetrazine for reducing cocaine use.

Functional foods: How functional are they? A case report of supplement-induced psychosis.

There is rising evidence of patients' use of alternative and complementary medicine. The percentage of the U.S. population who used at least one dietary supplement increased from 42% in 1988-1994 to 53% in 2003-2006. We present a case of an Asian female in her 40s, with no previous psychiatric illness, who presented to the emergency room following a brief psychotic episode, during which she self-amputated the tips of her fingers, after using multivitamins and herbal supplements including ginseng, gui yuan rou (Chinese herb), astaxanthin, goji (Chinese fruit), selenium, saw palmetto, grape seed extract, citrus bioflavanoid, lutein (zeaxantin), resvexatrol, sun chlorella, spirulina powder, phytoceramides, phytoestrogen, glucosatrin, bromelain plus, and American bee pollen. Comprehensive laboratory workup, drug screening, and diagnostic imaging were negative. Vital signs were stable. Other than the amputated finger tips, the remainder of her physical examination was unremarkable. Her mental status improved significantly after treatment with risperidone 1 mg twice daily, during a five-day psychiatric hospitalization. This case draws attention to the fact that supplements have the potential of producing frank psychosis and require close monitoring and study by physicians.